The averted infections ratio: a novel measure of effectiveness of experimental HIV pre-exposure prophylaxis agents

Abstract

There is clear evidence that tenofovir disoproxil fumarate combined with emtricitabine (TDF-FTC) is a highly efficacious oral pre-exposure prophylaxis agent for preventing the acquisition of HIV. This has consequences for the design and analysis of trials evaluating experimental pre-exposure prophylaxis regimens, which now generally include an active-control TDF-FTC arm rather than a placebo arm as a comparator. We point out major problems in the interpretation of the primary measure of effectiveness proposed for these trials, namely the ratio of the HIV incidence rates in the experimental agent and TDF-FTC arms. We argue that valid interpretation requires an assumption about one of two parameters: either the incidence rate that trial participants would have experienced had they not received pre-exposure prophylaxis or the effectiveness of the TDF-FTC within the trial. However, neither parameter is directly observed due to the absence of a no-treatment arm, requiring the use of external evidence or subjective judgement. We propose an alternative measure of effectiveness based on the concept of “averted infections”, which incorporates one of these parameters. The measure is simple to interpret, has clinical and public health relevance, and is a natural “preservation of effect” criterion for assessing statistical non-inferiority. Its adoption would also allow the use of smaller sample sizes, currently a major barrier to the evaluation of experimental pre-exposure prophylaxis regimens.

Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials

“…A more sophisticated estimator using a Nelson-Aalen estimator is described in [17]. Another formulation like the 'averted infections ratio' could be used alternatively [89]. Our simple measure can be interpreted as the total fraction of participants at the end of the trial that would likely have been infected but were instead protected due to VRC01.…”

Handling an uncertain control group event risk in non-inferiority trials: non-inferiority frontiers and the power-stabilising transformation

“…We have considered only binary outcomes, with risk differences and risk ratios as effect measures. Our approach could easily incorporate other effect measures, such as odds ratios or averted infection ratios 15 , either to define an alternative non-inferiority frontier, or as the basis of a "conditionally modify margin" procedure assuming the power-stabilising frontier.…”

Taking stock of the present and looking ahead: envisioning challenges in the design of future HIV prevention efficacy trials

“…Measuring efficacy instead on an absolute risk scale could be advantageous, since precision would be influenced by the number of person-years at risk, and therefore smaller sample sizes may be needed to ensure adequate power and precision. 47,48 This and other attributes of the statistical performance of alternative efficacy measures deserve further exploration by statisticians (see Box 2).…”